Preparation of Pharmaceutical Dosage Forms Containing Iron (III) Salts

ABSTRACT

The present invention provides a method for designing a ferric pyrophosphate citrate complex composition containing pyrophosphate, citrate, ferric, sodium, and sulfate ions and calculating and adjusting each salt needed based on a choice of salts that contain the above ions and a desired concentration of each ion in the final product. The present invention also provides a process for preparing a pharmaceutical dosage form of ferric pyrophosphate citrate complex composition in liquid form which is ready to be administrated to patients in need and which maintains the mass balance of ion sources throughout the process.

FIELD OF THE INVENTION

The present invention relates to the preparation of pharmaceutical dosage forms containing iron (III) salts.

BACKGROUND OF THE INVENTION

Iron plays an essential role in many biological processes. Complexes of iron with biomolecules are required for many vital physiologic processes, such as transport of oxygen throughout the body, synthesis of hormones, metabolism, detoxification and electron transport. It is recognized that iron deficiency can lead to many serious pathological conditions. Public health authorities recommend iron supplementation to avoid anemia caused by iron deficiency. Many forms of supplements, from elemental iron, to various salts and complexes of iron are used for oral administration.

In more severe cases of anemia, such as in patients with chronic diseases and patients undergoing dialysis, iron supplements in solution are provided by intravenous route. Many of these iron compounds have complex structures where iron atoms are held in a core surrounded by organic or inorganic moieties. Although most of these iron complexes have been known for a long time, commercial production of these compounds has been challenging and has required extensive technological developments. Typically these complexes are first made and isolated as solid and then made into a dosage form as a solution. However, the processes that involve isolation of the solid complex do not provide a product of uniform composition.

U.S. Pat. No. 7,816,404 discloses a process of preparing a water soluble ferric pyrophosphate citrate chelate by precipitating it from a liquid composition. Experimental details in Table 11 of U.S. Pat. No. 7,816,404 reveal that the solid ferric pyrophosphate citrate chelate takes about 60% by weight of the liquid composition. Extra Fe³⁺ may be in the form of other salts, impurities, or remains in mother liquor and thus lost in the liquid composition. The precipitated ferric pyrophosphate citrate chelate needs to be dried in an oven. Extra precautions are required during the drying to minimize decomposition of the chelate such as conversion of pyrophosphate to phosphate due to heat. It is reported that the chelate contains phosphate in an amount of 2% or less by weight.

The process disclosed in U.S. Pat. No. 7,816,404 cannot provide a product of uniform composition. Based on the data provided in Tables 10 and 11 of U.S. Pat. No. 7,816,404, we calculate percent of variations of citrate and pyrophosphate in different lots, shown as below:

Batch % Fe % Citrate % Pyrophosphate No. Scale Assay¹ Assay¹ Variance² Assay¹ Variance² 4864  1 g 8.6 28.1 +6.22 11.8 −8.24 4865  2 g 8.8 37.5 +15.03 12.7 −7.81 4866  2 g 10.2 32.6 +6.55 13.8 −9.97 4868 10 g 9.6 30.3 +5.78 14.1 −8.27 4869 10 g 9.7 27.7 +3.02 13.2 −9.405 511516 10 g 10.83 22.4 −5.16 18.3 −6.94 511517 10 g 10.27 23.5 −2.63 17.3 −6.63 511913 25 g 10.23 23.4 −2.63 17.7 −6.14 ¹Weight percents shown here are from the specific Batch No. in Tables 10 and 11 of Pat. No. 7,816,404. ²Variance in citrate and pyrophosphate content is the difference in percent composition of isolated solid from the expected amount for Fe₄(citrate)₃(pyrophosphate)₃ on the basis of assay for % Fe. It is marked as “+” if weight percent in the sample is more than expected and marked as “−” if weight percent in sample is less than expected.

The above calculations show that even when the assay for % Fe for the lots are similar, there are big differences in citrate and pyrophosphate content from lot to lot. Actually on scale up, the citrate goes from excess to deficiency, even though the same excess of citrate is used in the chemical reaction. It is obvious from these data that further scale up to commercial scale will be very challenging.

Without wishing to be bound by theory, the inconsistency in net output with scale given same input, as observed in the prior art process, may be caused by loss on drying and degradation (e.g., from pyrophosphate to phosphate) due to heat, as required by the process of U.S. Pat. No. 7,816,404.

U.S. Pat. No. 8,178,709 reports a method of preparation of a water soluble ferric citrate chelate with varying amounts of pyrophosphate and sodium, which indicates that non-essential components make up a significant weight of the bulk mass. This material is prepared by air oxidation of Fe²⁺ to Fe³⁺ and requires 3-7 days to complete the reaction in laboratory. The composition that enables the oxidation is essentially free of sulfate. Because the product is light sensitive, the oxidation process has to be run in dark. Given the long reaction time, scaling up the oxidation process for commercial production is very challenging and requires many operational controls.

Therefore, there is a need for an operationally simple procedure for preparing solutions of iron salt that can readily be administered.

SUMMARY OF THE INVENTION

The inventors of this application have found a way to avoid isolating the solid of iron (III) containing complex during a manufacturing process. In one aspect, the present invention provides a process of directly preparing a dosing solution containing a soluble form of iron (III). The dosing solution may contain an iron (III) concentration of between 10-250 mM. The iron (III) solution may be further diluted if needed.

One novel feature of the process is that the mass balance is maintained because all the components of a final product mixture containing ferric pyrophosphate citrate complex and other salts are same in mass balance as input material. As a result, the process is suitable for scaling up the production of the final product mixture.

Because the mass balance of the input material is maintained in the final product with respect to each ion, it is possible to design the iron (III) containing complex and/or calculate the actual percent of each ion in the final product.

In another aspect, the present invention provides a method for designing a ferric pyrophosphate citrate complex composition containing pyrophosphate, citrate, ferric, sodium, and sulfate ions and calculating each salt needed based on a choice of salts that contain the above ions and a desired concentration of each ion in the final product. The present invention may further provide a process for preparing a ferric pyrophosphate citrate complex composition by incorporating the design method.

In yet another aspect, the present invention provides a method for determining ion concentrations of a ferric pyrophosphate citrate complex composition based on the actual weight of each salt added in the composition and percent by weight of each ion in each salt.

In a further aspect, the present invention provides a method for adjusting the amount of each salt needed to make a ferric pyrophosphate citrate complex composition so that each ion falls in a preset range by incorporating the design method and the method for determining ion concentrations of a ferric pyrophosphate citrate complex composition.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic view of a method for designing a ferric pyrophosphate citrate complex composition containing pyrophosphate, citrate, ferric, sodium, and sulfate ions.

FIG. 2 is a schematic view of a method for determining ion concentrations of a ferric pyrophosphate citrate complex composition.

FIG. 3 is a schematic view of a method for designing or adjusting a ferric pyrophosphate citrate complex composition comprising pyrophosphate, citrate, ferric, sodium, and sulfate ions.

DETAILED DESCRIPTION OF THE INVENTION

In one aspect, the present invention provides a process of directly preparing a dosing solution containing a soluble form of iron (III) at a concentration of between about 10-250 mM. By the term “mM”, it refers to a concentration unit of milimole/liter (i.e., 1×10⁻³ mol/L).

The process comprises the steps of: mixing a citrate ion source, a pyrophosphate ion source, and a ferric (i.e., iron (III)) ion source in an aqueous based vehicle carrier to form a solution of a ferric pyrophosphate citrate complex, without isolating a solid form of ferric pyrophosphate citrate complex. In other words, the ferric pyrophosphate citrate complex remains in solution throughout the process and can be directly used as a dosage form, with or without a further dilution. In some embodiments, the process comprises the step of mixing a sodium ion source, wherein the number of sodium ions in a molecule of sodium ion source is 1, 2, 3, or 4. For example, monosodium citrate contains one (1) sodium ion; disodium citrate contains two (2) sodium ions, trisodium citrate contains three (3) sodium ions; tetrasodium pyrophosphate contains four (4) sodium ions. In some other embodiments, the process further comprises the step of mixing a sulfate ion source. A ferric pyrophosphate citrate complex is formed when all of the relevant ions are added. The ferric pyrophosphate citrate complex comprises ferric, pyrophosphate, and citrate ions. Additionally, it may comprises sodium and sulfate ions.

Suitable ferric ion sources for the present invention include, but are not limited to, ferric sulfate, ferric sulfate hydrate, ferric chloride, ferric ammonium sulfate, a hydrate thereof, and a combination thereof. Suitable citrate ion sources may be selected from a group consisting of citric acid, monosodium citrate, disodium citrate, trisodium citrate, a hydrate thereof, and a combination thereof. Suitable pyrophosphate ion sources may be selected from a group consisting of disodium dihydrogen pyrophosphate, tetrasodium pyrophosphate, a hydrate thereof, and a combination thereof. Suitable sodium ion sources may include, but are not limited to, monosodium citrate, disodium citrate, trisodium citrate, disodium dihydrogen pyrophosphate, tetrasodium pyrophosphate, sodium hydroxide, sodium carbonate, sodium bicarbonate, sodium sulfate, and an applicable hydrate thereof. Suitable sulfate ion sources may include, but are not limited to, ferric sulfate, sodium sulfate, ferric ammonium sulfate, and a hydrate thereof. In one ferric pyrophosphate citrate complex composition, the sodium and sulfate ions may also be provided by up to three compounds which individually provides either sodium or sulfate ions.

According to some preferred embodiments, the ferric pyrophosphate citrate complex comprises a ferric ion in an amount from about 7.5 to about 9% by weight, a citrate ion in an amount from about 15 to about 22% by weight, a pyrophosphate ion in an amount from about 15 to about 22% by weight; a sodium ion in an amount from about 18 to about 25% by weight; and a sulfate ion in an amount of from about 20 to about 35% by weight. Unless stated otherwise, the percent by weight (% by wt.) used herein is based on an anhydrous basis of the total ions added into the composition.

In some embodiments, to mix the ions, it is preferable to prepare a ferric ion solution separately, and add the ferric ion solution to the rest of other ion solution. Because a ferric ion coexists with its counter ion in a salt, forming a ferric ion solution means to dissolve a ferric salt in a solvent. To facilitate the mixing, the resulting mixture may be heated up slightly above room temperature, for example, to about 50° C. and maintained at the temperature for a certain period of time, followed by cooling the solution to room temperature or below. To prevent degradation of the drug product, the solution temperature should not be raised too high or be kept at an elevated temperature for too long. The resulting mixture is preferably stored at room temperature or lower than room temperature. Prior to use, the resulting mixture may be diluted by adding water or an aqueous base solution to adjust pH thereof as well.

The process of the present invention provides an elegant way of making the desired final finished product drug composition without involving a precipitation with a solvent or a subsequent drying step. Thus, potential degradation of the drug complex is avoided. The prepared solution has no or essentially no phosphate ions. Additionally, the entire process is in situ and in one-pot (i.e., one unit operation, without the need to transfer reaction container). The prepared solution is ready for testing and may be directly used for filling of product through filtration into suitable containers. In contrast, the prior art process requires isolation, drying, and testing of a solid drug complex, followed by dissolution of the solid drug complex in water to prepare the desired dosage form. Thus, the process of the present invention is novel by using a one-solution phase processing to obtain a desired final drug formulation without isolation, drying, and additional solution preparation.

The drug complex composition prepared by the process has all citrate ions effectively used in forming the drug product complex. The yield and cost of the process is very economical given the nature of the process with a few number of steps involved and no loss of material in handing, compared to the prior art processes.

In another aspect, the present invention provides a pharmaceutical composition of a ferric pyrophosphate citrate complex prepared by the above mentioned process.

In yet another aspect, the present invention provides a method for treating iron deficiency comprising the step of administering to a subject in need a therapeutically effective amount of the ferric pyrophosphate citrate complex composition.

In a further aspect, the present invention provides a method for designing a ferric pyrophosphate citrate complex composition, a method for determining ion concentrations of a ferric pyrophosphate citrate complex composition, and a method for adjusting the amount of each salt needed to make a ferric pyrophosphate citrate complex composition so that each ion falls in a preset ion concentration range. The methods are derived from weight relationships of different ions and salts (i.e., ion sources) in the compositions.

According to one embodiment, an ionic composition of ferric citrate pyrophosphate comprises Fe₂(SO₄)₃, Na₃₋Citrate, Na₄Pyrophosphate, and Na₂SO₄. The weight % of each ion in each salt can be summarized as follows:

Mol. Mol. Name Formula Wt. Percent Percent Ferric Sulfate Fe₂(SO₄)₃ 400.1 27.99% Fe 72.01% SO₄ Trisodium Na₃-Citrate 258.07 26.73% Na 73.27% Citrate Citrate Tetra sodium Na₄P₄O₇ 265.9 34.58% Na 65.42% P₄O₇ Pyrophosphate Sodium Na₂SO₄ 142.1 32.37% Na 67.63% SO₄ Sulfate

From the above table, one may calculate the amount of each ion in the final composition based on the amount of each salt used according to the following equations:

Wt. Fe=Wt. Fe₂(SO₄)₃×0.2799  (1)

Wt. Citrate=Wt. Na₃−Citrate×0.7327  (2)

Wt. P₄O₇=Wt. Na₄P₄O₇×0.6542  (3)

Wt. Na=Wt. Na₃−Citrate×0.2673+Wt. Na₄P₄O₇×0.3458+Wt. Na₂SO₄×0.3237  (4)

Wt. SO₄=Wt. Fe₂(SO₄)₃×0.7201+Wt. Na₂SO₄×0.6763  (5)

(wherein “X” means the operation “times”; wherein Wt. Fe means the weight of ferric ion; wherein Wt. Fe₂(SO₄)₃ means the weight of ferric sulfate, etc.).

One may further calculate percentage of each ion in the product according to the following equations:

% Fe=Wt. Fe×100/(Wt. Fe₂(SO₄)₃+Wt. Na₃−Citrate+Wt. Na₄P₄O₇+Wt. Na₂SO₄)  (6)

% Citrate=Wt. Citrate×100/(Wt. Fe₂(SO₄)₃+Wt. Na₃−Citrate+Wt. Na₄P₄O₇+Wt. Na₂SO₄)  (7)

% P₄O₇=Wt. P₄O₇×100/(Wt. Fe₂(SO₄)₃+Wt. Na₃−Citrate+Wt. Na₄P₄O₇+Wt. Na₂SO₄)  (8)

% Na=Wt. Na×100/(Wt. Fe₂(SO₄)₃+Wt. Na₃−Citrate+Wt. Na₄P₄O₇+Wt. Na₂SO₄)  (9)

% SO₄=Wt. SO₄×100/(Wt. Fe₂(SO₄)₃+Wt. Na₃−Citrate+Wt. Na₄P₄O₇+Wt. Na₂SO₄)  (10)

According to another embodiment, an ionic composition of ferric citrate pyrophosphate comprises Fe₂(SO₄)₃, Na₂₋Citrate, Na₄Pyrophosphate, and Na₂SO₄. The weight % of each ion in each salt can be summarized as follows:

Mol. Mol. Name Formula Wt. Percent Percent Ferric Sulfate Fe₂(SO₄)₃ 400.1 27.99% Fe 72.01% SO₄ Disodium Na₂-Citrate 236 19.49% Na  80.5% Citrate Citrate Tetra sodium Na₄P₄O₇ 265.9 34.58% Na 65.42% P₄O₇ Pyrophosphate Sodium Na₂SO₄ 142.1 32.37% Na 67.63% SO₄ Sulfate

Using the information in the above table, one can calculate the amount of each component required in the final mixture for the desired composition by the following equations:

0.28×Wt. Fe₂(SO₄)₃=(desired Fe %/100)×(Wt. Fe₂(SO₄)₃+Wt. Na₂−Citrate+Wt. Na₄P₄O₇+Wt. Na₂SO₄)  (11)

0.805×Wt. Na₂−Citrate=(desired citrate %/100)×(Wt. Fe₂(SO₄)₃+Wt. Na₂−Citrate+Wt. Na₄P₄O₇+Wt. Na₂SO₄)  (12)

0.654×Wt. Na₄P₄O₇=(desired P₄O₇%/100)×(Wt. Fe₂(SO₄)₃+Wt. Na₂−Citrate+Wt. Na₄P₄O₇+Wt. Na₂SO₄)  (13)

0.72×Wt. Fe₂(SO₄)₃+0.676×Wt. Na₂SO₄=(desired SO₄%/100)×(Wt. Fe₂(SO₄)₃+Wt. Na₂−Citrate+Wt. Na₄P₄O₇+Wt. Na₂SO₄)  (14)

0.195×Wt. Na₂−Citrate+0.346×Wt. Na₄P₄O₇+0.324×Wt. Na₂SO₄=(desired Na %/100)×(Wt. Fe₂(SO₄)₃+Wt. Na₂−Citrate+Wt. Na₄P₄O₇+Wt. Na₂SO₄)  (15)

The amounts of various salts needed can be calculated as follows based on the equations (11) to (13):

Wt. Fe2(SO4)3=(desired Fe %/100)/0.28×(Wt. Fe2(SO4)3+Wt. Na2−Citrate+Wt. Na4P4O7+Wt. Na2SO4)

Wt. Na₂−Citrate=(desired citrate %/100)/0.805×(Wt. Fe₂(SO₄)₃+Wt. Na₂−Citrate+Wt. Na₄P₄O₇+Wt. Na₂SO₄)

Wt. Na₄P₄O₇=(desired P4O7%/100)/0.654×(Wt. Fe₂(SO₄)₃+Wt. Na₂−Citrate+Wt. Na₄P₄O₇+Wt. Na₂SO₄)

The amount of Na₂SO₄ may be calculated based on the equations (14) and (15).

Accordingly, the present invention provides a method for designing a ferric pyrophosphate citrate complex composition as illustrated in FIG. 1. The method 100 comprises the steps of:

-   -   (1) setting a desired percent by weight of each ion (step 102);     -   (2) providing one ferric salt (A) for supplying ferric ion, one         citrate salt (B) for supplying citrate ion, one pyrophosphate         salt (C) supplying pyrophosphate ion, and at least one salt (D)         for supplying sodium ion and sulfate ion to the composition         (step 104);     -   (3) calculating percent by weight of ferric ion in a molecule of         the ferric salt (A), percent by weight of citrate ion in a         molecule of the citrate salt (B), and percent by weight of         pyrophosphate ion in a molecule of the pyrophosphate salt (C)         (step 106);     -   (4) calculating the amount of the ferric salt (A) needed in the         mixing step (step 108) based on the formula:

weight of the ferric salt (A)=the desired weight of ferric ion/the percent by weight of ferric ion in a molecule of the ferric salt (A);

-   -   (5) calculating the amount of the citrate salt (B) needed in the         mixing step (step 110) based on the formula:

weight of the citrate salt (B)=the desired weight of citrate ion/the percent by weight of citrate ion in a molecule of the citrate salt (B);

-   -   (6) calculating the amount of the pyrophosphate salt (C) needed         in the mixing step (step 112) based on the formula:

weight of the pyrophosphate salt (C)=the desired weight of pyrophosphate ion/the percent by weight of pyrophosphate ion in a molecule of the pyrophosphate salt (C);

-   -   (7) calculating the amount of sodium ion or sulfate ion         contributed by the salts (A), (B) and (C), subtracting these         amounts from the total desired percent by weight of sodium ion         or sulfate ion to calculate the amount of the salt (D) (step         114);         wherein the order of steps 108 to 112 is changeable among         themselves, and wherein the percent by weight (% by weight) is         based on an anhydrous basis of the ferric pyrophosphate citrate         complex. Instead of using a single salt (D) for providing sodium         ion and sulfate ion, multiple salts (D1, D2, D3, etc.) may be         used to provide sodium ion and sulfate ions.

In some embodiments, the desired percent by weight of each ion in step 102 may be a ferric ion in an amount from about 7.5 to about 9% by weight, a citrate ion in an amount from about 15 to about 22% by weight, a pyrophosphate ion in an amount from about 15 to about 22% by weight; a sodium ion in an amount from about 18 to about 25% by weight; and a sulfate ion in an amount of from about 20 to about 35% by weight.

In some embodiments, the sum total of percent by weight of pyrophosphate, citrate, ferric, sodium, and sulfate ions is greater than 90%. In some other embodiments, the sum total of percent by weight of pyrophosphate, citrate, ferric, sodium, and sulfate ions is greater than 95%. In further embodiments, the sum total of percent by weight of pyrophosphate, citrate, ferric, sodium, and sulfate ions is 100%. The above weight or % wt. is based on an anhydrous basis of the ferric pyrophosphate citrate complex. The complex contains no or essentially no phosphate ion. Without wishing to be bound by theory, the fact that the total % wt. is may not be 100% can be due to presence of minor impurities (such as sodium carbonate or bicarbonate in sodium sulfate, ferric chloride in ferric sulfate) in each salt or due to reasonable calculation errors while rounding off in each specific operation.

The present invention further provides a process for preparing a ferric pyrophosphate citrate complex composition comprising the steps of: designing the ferric pyrophosphate citrate complex composition using the design method; mixing the ferric salt (A), citrate salt (B), the pyrophosphate salt (C), and the fourth salt (D) in their respective calculated amounts in an aqueous based carrier.

The present invention also provides a method for determining ion concentrations of a ferric pyrophosphate citrate complex composition, as illustrated in FIG. 2. The method 200 comprises the steps of:

-   -   (a) providing more than one salts, wherein each salt provides at         least one of ferric cation, citrate anion, pyrophosphate anion,         sulfate anion and sodium cation for preparing a composition         (step 202);     -   (b) for each salt, calculating percent by weight of cation and         percent by weight of anion in a molecule of the salt (step 204);     -   (c) based on weight, in percent by weight, of each salt,         calculating a total of percent by weight of ferric ion (step         206), using the formula:

A total weight of ferric ion=weight of a first salt containing ferric ion X the percent by weight of ferric cation in a molecule of the first salt calculated in step 204+weight of a second salt containing ferric ion X the percent by weight of ferric cation in a molecule of the second salt calculated in step 204, if applicable, +weight of a third salt containing ferric ion X the percent by weight of ferric cation in a molecule of the third salt calculated in step 204, if applicable;

-   -   (d) calculating a total of weight of each of citrate anion,         pyrophosphate anion, sulfate anion, and sodium cation (step 208)         based on the same formula of the above (step 206), except the         ferric ion in the formula is to be substituted with the specific         anion or cation being calculated;         wherein the weight is based on an anhydrous basis of the ferric         pyrophosphate citrate complex.

Additionally, the present invention also provides a method for adjusting the amount of each salt needed to make a ferric pyrophosphate citrate complex composition so that each ion falls in a preset ion concentration range, as illustrated in FIG. 3. The method 300 comprises the steps of:

-   -   (a) setting a desired range of percent by weight of each ion         (step 302);     -   (b) picking one percent by weight of each ion within the desired         range of percent by weight of said ion (step 304);     -   (c) providing one ferric salt (A) for supplying ferric ion, one         citrate salt (B) for supplying citrate ion, one pyrophosphate         salt (C) supplying pyrophosphate ion, and at least one salt (D)         for supplying sodium ion and sulfate ion to the composition         (step 306);     -   (d) calculating the amounts of salts (A), (B), (C), and (D)         needed as described above (step 308);     -   (e) based on the amounts of the salts (A), (B), (C), and (D),         calculating a total of percent by weight of each ion if the         salts (A), (B), (C), and (D) are mixed (step 310);     -   (f) comparing (step 312) the calculated total percent by weight         of each ion of step 310 with the desired range of percent by         weight of each ion set of step 302;     -   (g) if the calculated total percent by weight of each and every         ion, as calculated in step 310, falls within the desired range         of said ion set in step 302, concluding that the amounts of the         salts (A), (B), (C), and (D), as calculated in step 308 is         suitable for use in preparing the ferric pyrophosphate citrate         complex composition—This step is referred as step 314 in FIG. 3;         or         -   if the calculated total percent by weight of any ion, as             calculated in step 310, is outside the desired range of the             ion in step 302, adjusting the amounts of one or more of the             salts, and repeating steps 304 to 312, until the calculated             total percent by weight of each and every ion, as calculated             in 310, falls with the desired range of said ion set in             302—This step is referred as step 316 in FIG. 3;

In some embodiments, the desired percent by weight of each ion in step 302 may be a ferric ion in an amount from about 7.5 to about 9% by weight, a citrate ion in an amount from about 15 to about 22% by weight, a pyrophosphate ion in an amount from about 15 to about 22% by weight; a sodium ion in an amount from about 18 to about 25% by weight. The percent by weight of each ion picked in step 304 is in the above referred range of the corresponding ion. In preferred embodiments, the percent by weight of each ion picked in step 304 is in a middle point of the desired range percent by weight of said ion.

Preferably, the above methods can utilize a computer system to automatically calculate the values once one variable is changed. Further, the computer system may have a hardware to allow a user to provide input of variables. The variables may be choices of salts or compounds that provide ion sources, desirable ion concentrations, and the amounts of salts.

The following examples further describe the materials and methods used in carrying out the invention. The examples are not intended to limit the invention in any manner.

Example 1

To 375 ml of water, 8.33 g of tribasic sodium citrate dihydrate, 15.63 g of Sodium pyrophosphate decahydrate, and 3.47 g of sodium sulfate were added. The mixture was stirred at ambient temperature until all the solids dissolved. In another beaker 12.175 g of ferric sulfate was dissolved in 100 ml of water and the brown solution was added to the solution of sodium salts prepared above. The reaction mixture became light green and the pH was 3.8. After heating the reaction at 50° C. for 1.5 hours, the reaction was cooled and diluted with water to a total volume of 500 ml. The pH of this solution was 3.52. The process may further include a step of adjusting the pH value of the solution.

Examples 2-6

Using the equations (1) to (15), the inventors of the application are able to generate spreadsheet files to calculate contribution of each salt to the final composition of each ionic moiety. With these calculations, the inventors of the application can produce any desired solution composition.

Example 2 shows a spreadsheet calculating compositions of Iron PypCitrate complex 1 on anhydrous basis.

Ferric Sulfate A Fe2(SO4)3 Total Fe 0.2793 SO4 0.7207 A = 2F + 3S 399.86 111.69 288.19 Disodium Citrate Na2 Citrate Total Na 0.1948 Citrate 0.8052 B = 2N + 1C 236.09 45.98 190.11 Sodium Pyrophos C Na2 Pyrophos Total Na 0.3458 Pyrophos 0.6542 C = 4N + 1P 265.9 91.96 173.94 Sodium Sulfate D Na2 SO4 Total Na 0.3237 SO4 0.6763 D = 2N + 1S 142.04 45.98 96.06 Total Weight A 31 Fe 8.66 SO4 22.34 31.33 B 25 Na 4.87 Citrate 20.13 24.38 C 31.5 Na 10.89 Pyrophos 20.61 30.03 D 12.5 Na 4.05 SO4 8.45 9.76 A + B + C + D= 100 Provided Fe Cit PyroPhs SO4 Na Total 8.25 18.5 18.5 27.5 21.5 94.25 8.75 19.63 19.63 29.18 22.81 100 Calculated from the table Total Fe Cit PyroPhs SO4 Na 100.00 8.66 20.13 20.61 30.80 19.81

Example 3 shows a spreadsheet calculating compositions of Iron PypCitrate 2 with 5.5% water to match with the label claim.

Ferric Sulfate A Fe2(SO4)3 Total Fe 0.2793 SO4 0.7207 A = 2F + 3S 399.88 111.69 288.19 Disodium Citrate Na2 Citrate Total Na 0.1948 Citrate 0.8052 B = 2N + 1C 236.09  45.98 190.11 Sodium Pyrophos C Na2 Pyrophos Total Na 0.3458 Pyrophos 0.6542 C = 4N + 1P 265.9   91.96 173.94 Sodium Sulfate D Na2 SO4 Total Na 0.3237 SO4 0.6763 D = 2N + 1S 142.04  45.98  96.06 Total Weight A 29 Fe 8.10 SO4 20.90 31.33 B 23 Na 4.48 Citrate 18.52 24.38 C 29 Na 10.03 Pyrophos 18.97 30.03 D 13.5 Na 4.37 SO4 9.13 9.76 A + B + C + D= 94.5 Target wt Wt should be About wt For Compound-A A = 2F + 3S Fe 8.25 A 29.5372 0.2793A + 0.7207A For Compound-B 2N + 1C Citrate 18.5 B 22.9744 0.1948B + 0.8052B For Compound-C 4N + 1P Pyrophos 18.5 C 28.2807 0.3458C + 0.6542C For Compound-D D = 100 − (A + B + C) D 19.2077 100 Provided Fe Cit PyroPhs SO4 Na Total 8.25 18.5 18.5 27.5 21.5 94.25 8.75 19.63 19.63 20.18 22.81 100 Calculated from Below table Total Fe Cit PyroPhs SO4 Na 94.50 8.10 18.52 18.97 30.03 18.88

Example 4 shows a spreadsheet calculating compositions of Iron PypCitrate 3 by use of Trisodium Citrate to increase amount of Na.

Ferric Sulfate A Fe2(SO4)3 Total Fe 0.2793 SO4 0.7207 A = 2F + 3S 399.88 111.69 288.19 Trisodium Citrate Na3 Citrate Total Na 0.2673 Citrate 0.7327 B = 3N + 1C 258.07 68.97 189.1 Sodium Pyrophos C Na2 Pyrophos Total Na 0.3458 Pyrophos 0.6542 C = 4N + 1P 265.9 91.96 173.94 Sodium Sulfate D Na2 SO4 Total Na 0.3237 SO4 0.6763 D = 2N + 1S 142.04 45.98 96.06 Sodium Hydroxide E NaOH Total Na 0.5750 OH 0.4250 E = 1N + 1OH 40 23 17 Total Weight A 29.5 Fe 8.24 SO4 21.26 31.33 B 25.25 Na 6.75 Citrate 18.50 24.38 C 28.28 Na 9.78 Pyrophos 18.50 30.03 D 9.25 Na 2.99 SO4 6.26 9.76 E 3.45 Na 1.98 OH 1.47 A + B + C + D= 95.73 Target wt Wt should be About wt For Compound-A A = 2F + 3S Fe 8.25 A 29.5372 0.2793A + 0.7207A For Compound-B 2N + 1C Citrate 18.5 B 25.2475 0.1948B + 0.8052B For Compound-C 4N + 1P Pyrophos 18.5 C 28.2807 0.3458C + 0.6542C For Compound-D 94.25 − (A + B + C) 11.1846 D = 100 − (A + B + C) D 16.9346 100 Provided Fe Cit PyroPhs SO4 Na Phosphate 7.5-9 15-22 15-22 20-35 18-25 <2 Total 8.25 18.5 18.5 27.5 21.5 94.25 8.75 19.63 19.63 20.18 22.81 100 Calculated from Below table Total Fe Cit PyroPhs SO4 Na 94.26 8.24 18.50 18.50 27.52 21.51

Example 5 shows a spreadsheet calculating compositions of Iron PypCitrate 4 by use of NaOH in addition to Na₂SO₄.

portion portion Ferric Sulfate A Fe2(SO4)3 Total Fe 0.2793 SO4 0.7207 A = 2F + 3S 399.88 111.69 288.19 Trisodium Citrate Na3 Citrate Total Na 0.2673 Citrate 0.7327 B = 3N + 1C 258.07 68.97 189.1 Sodium Pyrophos C Na2 Pyrophos Total Na 0.3458 Pyrophos 0.6542 C = 4N + 1P 265.9 91.96 173.94 Sodium Sulfate D Na2 SO4 Total Na 0.3237 SO4 0.6763 D = 2N + 1S 142.04 45.98 96.06 Sodium Hydroxide E NaOH Total Na 0.5750 OH 0.4250 E = 1N + 1OH 40 23 17 Provided Fe Cit PyroPhs SO4 Na Phosphate Range 7.5-9 15-22 15-22 20-35 18-25 <2 Total 8.25 18.5 18.5 27.5 21.5 94.25 8.75 19.63 19.63 29.18 22.81 100 0 g NaOH Total Weight A 29.5 Fe 8.24 SO4 21.26 31.33 B 25.25 Na 6.75 Citrate 18.50 24.38 C 28.25 Na 9.77 Pyrophos 18.48 30.03 D 11.25 Na 3.64 SO4 7.61 9.76 E 0 Na 0.00 OH 0.00 A + B + C + D= 94.25 Calculated from Below table Total Fe Cit PyroPhs SO4 Na 94.25 8.24 18.50 18.48 28.67 20.16 0 g NaOH but increased sodium pyrophosphate Total Weight A 29.5 Fe 8.24 SO4 21.26 31.33 B 25.25 Na 6.75 Citrate 18.50 24.38 C 29 Na 10.03 Pyrophos 18.97 30.03 D 10.5 Na 3.40 SO4 7.10 9.76 E 0 Na 0.00 OH 0.00 A + B + C + D= 94.25 Calculated from Below table Total Fe Cit PyroPhs SO4 Na 94.25 8.24 18.50 18.97 28.36 20.18 1 g NaOH Total Weight A 29.5 Fe 8.24 SO4 21.26 31.33 B 25.25 Na 6.75 Citrate 18.50 24.38 C 28.25 Na 9.77 Pyrophos 18.48 30.03 D 10.7 Na 3.46 SO4 7.24 9.76 E 1 Na 0.58 OH 0.43 A + B + C + D= 94.7 Calculated from Below table Total Fe Cit Pyrophos SO4 Na 94.28 8.24 18.50 18.48 28.50 20.56 2 g NaOH Total Weight A 29.5 Fe 8.24 SO4 21.26 31.33 B 25.25 Na 6.75 Citrate 18.50 24.38 C 28.25 Na 9.77 Pyrophos 18.48 30.03 D 10.1 Na 3.27 SO4 6.83 9.76 E 2 Na 1.15 OH 0.85 A + B + C + D= 95.1 Calculated from Below table Total Fe Cit PyroPhs SO4 Na 94.25 8.24 18.50 18.48 28.09 20.94 >3 g NaOH (with Exact proportion as required) Total Weight A 29.5 Fe 8.24 SO4 21.26 31.33 B 25.25 Na 6.75 Citrate 18.50 24.38 C 28.28 Na 9.78 Pyrophos 18.50 30.03 D 9.25 Na 2.99 SO4 6.26 9.76 E 3.45 Na 1.98 OH 1.47 A + B + C + D= 95.73 Calculated from Below table Total Fe Cit PyroPhs SO4 Na 94.26 8.24 18.50 16.50 27.52 21.51

Example 6 shows a spreadsheet calculating compositions of Iron PypCitrate 5 by use of Ferric Citrate and Ferric Pyrophosphate.

portion portion Ferric Sulfate A Fe2(SO4)3 Total Fe 0.2793 SO4 0.7207 A = 2F + 3S 399.88 111.69 288.19 Trisodium Citrate Na3 Citrate Total Na 0.2673 Citrate 0.7327 B = 3N + 1C 258.07 68.97 189.1 Sodium Pyrophos C Na2 Pyrophos Total Na 0.3458 Pyrophos 0.6542 C = 4N + 1P 265.9 91.96 173.94 Sodium Sulfate D Na2 SO4 Total Na 0.3237 SO4 0.6763 D = 2N + 1S 142.04 45.98 96.05 Sodium Hydroxide E NaOH Total Na 0.5750 OH 0.4250 E = 1N + 1OH 40 23 17 Ferric Pyrophosphate F Fe4 Pyrophos Total Fe 0.2998 Pyrophos 0.7002 F = 4F + 3P 745.21 223.38 521.83 Ferric Citrate G Fe Citrate (C6H 

Total Fe 0.2280 Citrate 0.7720 G = 1F + 1C 244.94 55.845 189.1 Provided Fe Cit PyroPhs SO4 Na Phosphate Range 7.5-9 15-22 15-22 20-35 18-25 <2 Total 8.25 18.5 18.5 27.5 21.5 94.25 8.75 19.63 19.63 29.18 22.81 100 Ferric Citrate & Ferric Sulfate Total Weight Fe2(SO4)3 9.95 Fe 2.78 SO4 7.17 Na3 Citrate 0 Na 0.00 Citrate 0.00 Na2 Pyrophos 28.25 Na 9.77 Pyrophos 18.48 Na2 SO4 32.05 Na 10.37 SO4 21.68 NaOH 0 Na 0.00 OH 0.00 Fe4 Pyrophos 0 Fe 0.00 Pyrophos 0.00 Fe Citrate 24 Fe 5.47 Citrate 18.53 (C6H5FeO7) Total wt= 94.25 Calculate from Below table Total Fe Cit PyroPhs SO4 Na 94.25 8.25 18.53 18.48 28.85 20.15 Ferric pyrophosphate Total Weight Fe2(SO4)3 0 Fe 0.00 SO4 0.00 Na3 Citrate 25.25 Na 6.75 Citrate 18.50 Na2 Pyrophos 0 Na 0.00 Pyrophos 0.00 Na2 SO4 41.5 Na 13.43 SO4 28.07 NaOH 0 Na 0.00 OH 0.00 Fe4 Pyrophos 27.51 Fe 8.25 Pyrophos 19.26 Fe Citrate 0 Fe 0.00 Citrate 0.00 (C6H5FeO7) Total wt= 94.26 Calculated from Below table Total Fe Cit PyroPhs SO4 Na 94.26 8.25 18.50 19.26 28.07 20.18 Ferric Sulfate Total Weight Fe2(SO4)3 29.5 Fe 8.24 SO4 21.26 Na3 Citrate 25.25 Na 6.75 Citrate 18.50 Na2 Pyrophos 28.25 Na 9.77 Pyrophos 18.48 Na2 SO4 11.25 Na 3.64 SO4 7.61 NaOH 0 Na 0.00 OH 0.00 Fe4 Pyrophos 0 Fe 0.00 Pyrophos 0.00 Fe Citrate 0 Fe 0.00 Citrate 0.00 (C6H5FeO7) Total wt= 94.25 Calculated from Below table Total Fe Cit PyroPhs SO4 Na 94.25 8.24 18.50 18.48 28.87 20.16

indicates data missing or illegible when filed

While the present teachings have been described above in terms of specific embodiments and examples, it is to be understood that they are not limited to those disclosed embodiments and examples. Many modifications to the embodiments and examples will come to mind to those skilled in the art to which this pertains, and which are intended to be and are covered by both this disclosure and the appended claims. It is intended that the scope of the present teachings should be determined by proper interpretation and construction of the appended claims and their legal equivalents, as understood by those of skill in the art relying upon the disclosure in this specification and the attached drawings. 

What is claimed is:
 1. A process for directly preparing a pharmaceutical dosage form of ferric pyrophosphate citrate complex composition comprising: mixing a citrate ion source, a pyrophosphate ion source, and a ferric ion source in an aqueous based vehicle carrier to form a solution, without isolation of a solid form of ferric pyrophosphate citrate complex, wherein the ferric pyrophosphate citrate complex remains in solution throughout the process; and wherein the ferric ion concentration is between about 10-250 mM.
 2. The process of claim 1, wherein the ferric pyrophosphate citrate complex composition further comprises a sodium ion.
 3. The process of claim 2, wherein the ferric pyrophosphate citrate complex composition further comprises a sulfate ion.
 4. The process of claim 2, wherein the sodium ion is provided by up to three different sodium compounds.
 5. The process of claim 3, wherein the sulfate ion is provided by up to three different sulfate compounds
 6. The process of claim 1, wherein the ferric ion source is selected from a group consisting of ferric sulfate, ferric sulfate hydrate, ferric chloride, ferric ammonium sulfate, a hydrate thereof, and a combination thereof; wherein the citrate ion source is selected from a group consisting of citric acid, monosodium citrate, disodium citrate, trisodium citrate, a hydrate thereof, and a combination thereof; and wherein the pyrophosphate ion source is selected from a group consisting of disodium dihydrogen pyrophosphate, tetrasodium pyrophosphate, a hydrate thereof, and a combination thereof.
 7. The process of claim 3, wherein the ferric ion is present in an amount from about 7.5 to about 9% by weight, the citrate ion is present in an amount from about 15 to about 22% by weight, and the pyrophosphate ion is present in an amount from about 15 to about 22% by weight; wherein the sodium ion is present in an amount from about 18 to about 25% by weight; wherein the sulfate ion is present in an amount of from about 20 to about 35% by weight; wherein the composition contains a phosphate ion of less than 2% by weight, and wherein the percent by weight is based on an anhydrous basis.
 8. A pharmaceutical composition of a ferric pyrophosphate citrate complex prepared by the process of claim
 1. 9. A method for treating iron deficiency comprising: administering to a subject in need a therapeutically effective amount of the ferric pyrophosphate citrate complex composition of claim
 8. 10. A method for designing a ferric pyrophosphate citrate complex composition containing pyrophosphate, citrate, ferric, sodium, and sulfate ions, said method comprising the steps of: (a) setting a desired percent by weight of each ion; (b) supplying one ferric salt (A) for providing ferric ion, one citrate salt (B) for providing citrate ion, one pyrophosphate salt (C) providing pyrophosphate ion, and up to three additional compounds (D1, D2 and D3) for providing sodium ion and sulfate ion to the composition; (c) calculating percent by weight of ferric ion in a molecule of the ferric salt (A), percent by weight of citrate ion in a molecule of the citrate salt (B), and percent by weight of pyrophosphate ion in a molecule of the pyrophosphate salt (C); (d) calculating the amount of the ferric salt (A) needed in the mixing step based on the formula: weight of the ferric salt (A)=the desired weight of ferric ion/the percent by weight of ferric ion in a molecule of the ferric salt (A); (e) calculating the amount of the citrate salt (B) needed in the mixing step based on the formula: weight of the citrate salt (B)=the desired weight of citrate ion/the percent by weight of citrate ion in a molecule of the citrate salt (B); (f) calculating the amount of the pyrophosphate salt (C) needed in the mixing step based on the formula: weight of the pyrophosphate salt (C)=the desired weight of pyrophosphate ion/the percent by weight of pyrophosphate ion in a molecule of the pyrophosphate salt (C); (g) calculating the amount of sodium ion or sulfate ion contributed by the salts (A), (B) and (C), subtracting these amounts from the total desired percent by weight of sodium ion or sulfate ion to calculate the amount of the compounds (D1, D2, D3); wherein the order of steps (d) to (f) is changeable among themselves, and wherein the percent by weight is based on an anhydrous basis.
 11. The method of claim 10, wherein the total percent by weight of pyrophosphate, citrate, ferric, sodium, and sulfate ions is greater than 90%.
 12. The method of claim 10, wherein in step (a) the desired percent by weight of each ion is a ferric ion in an amount from about 7.5 to about 9% by weight, a citrate ion in an amount from about 15 to about 22% by weight, a pyrophosphate ion in an amount from about 15 to about 22% by weight, a sodium ion in an amount from about 18 to about 25% by weight, and a sulfate ion in an amount of from about 20 to about 35% by weight.
 13. A process for preparing a ferric pyrophosphate citrate complex composition comprising the steps of: designing the ferric pyrophosphate citrate complex composition according to the method of claim 10; mixing the ferric salt (A), citrate salt (B), the pyrophosphate salt (C), and the fourth salt (D) in their respective calculated amounts in an aqueous based carrier.
 14. A method for determining ion concentrations of a ferric pyrophosphate citrate complex composition comprising the steps of: (a) providing more than one salts, wherein each salt provides at least one of ferric cation, citrate anion, pyrophosphate anion, sulfate anion and sodium cation for preparing a composition; (b) for each salt, calculating percent by weight of cation and percent by weight of anion in a molecule of the salt; (c) based on weight of each salt, calculating a total of weight of ferric ion, using the formula: A total of weight of ferric ion=weight of a first salt containing ferric ion X the percent by weight of ferric cation in a molecule of the first salt calculated in step (b)+weight of a second salt containing ferric ion X the percent by weight of ferric cation in a molecule of the second salt calculated in step (b), if applicable, +weight of a third salt containing ferric ion X the percent by weight of ferric cation in a molecule of the third salt calculated in step (b), if applicable; (d) calculating a total of weight of each of citrate anion, pyrophosphate anion, sulfate anion and sodium cation based on the same formula as in step (c), except the ferric ion in the formula is to be substituted with the specific anion or cation being calculated; wherein the percent by weight (% by weight) is based on an anhydrous basis.
 15. A method for designing a ferric pyrophosphate citrate complex composition containing pyrophosphate, citrate, ferric, sodium, and sulfate ions, said method comprising the steps of: (a) setting a desired range of percent by weight of each ion; (b) picking one percent by weight of each ion within the desired range of percent by weight of said ion; (c) providing one ferric salt (A) for supplying ferric ion, one citrate salt (B) for supplying citrate ion, one pyrophosphate salt (C) supplying pyrophosphate ion, and at least one salt (D) for supplying sodium ion and sulfate ion to the composition; (d) calculating the amounts of salts (A), (B), (C), and (D) needed according to claim 10; (e) based on the amounts of the salts (A), (B), (C), and (D), calculating a total weight of each ion if the salts (A), (B), (C), and (D) are mixed, according to claim 10; (f) comparing the calculated total percent by weight of each ion in step (e) with the desired range of percent by weight of each ion set in step (a); (g) if the calculated total percent by weight of each and every ion, as calculated in step (e), falls within the desired range of said ion set in step (a), concluding that the amounts of the salts (A), (B), (C), and (D), as calculated in step (d) is suitable for use in preparing the ferric pyrophosphate citrate complex composition; or if the calculated total percent by weight of an ion, as calculated in step (e), is outside the desired range of said ion in step (a), adjusting the amounts of one or more of the salts, and repeating steps (b) to (g), until the calculated total percent by weight of each and every ion, as calculated in step (f), falls within the desired range of said ion set in step (a); wherein the percent by weight (% by weight) is based on an anhydrous basis.
 16. The method of claim 15, wherein in step (a) the desired percent by weight of each ion is a ferric ion in an amount from about 7.5 to about 9% by weight, a citrate ion in an amount from about 15 to about 22% by weight, a pyrophosphate ion in an amount from about 15 to about 22% by weight, a sodium ion in an amount from about 18 to about 25% by weight, and a sulfate ion in an amount of from about 20 to about 35% by weight.
 17. The method of claim 16, wherein in step (b) the percent by weight of each ion picked is in the range of the corresponding ion.
 18. The method of claim 15, further comprising the step of designing a computer program to automate the process, wherein the process further comprises a step for allowing a user to input the amounts of one or more of the salts. 